The overall goal of the studies proposed in this revised exploratory R21 application is to further explore the anti-amyloidogenic role of D-pinitol, a traditional insulin sensitizer herbal agent, in Tg2576 mice that model Alzheimer's disease (AD) amyloid neuropathology. The studies are supported by the feasibility evidence suggesting that a mechanism by which D-pinitol may prevent AD neuropathology in the brain of Tg2576 mice is through the inhibition of beta-amyloid (A(B) peptide generation. This may occur through a mechanism that prevents the generation of the gamma-CTF from amyloid precursor protein (APR), which is an index of gamma-secretase activity, without influencing normal Notch processing. Most interestingly, we also found that D-pinitol may prevent AB peptide generation and gamma-secretase at concentrations as low as 10 uM without evidence of cellular toxicity. Thus, it is possible that D-pinitol, in addition to its potential anti-amylolidogenic role as insulin-sensitizing agent, may also prevent AB peptide generation through direct modulation of a mechanism involved in gamma-secretase activation. Based on this new exciting evidence, the studies proposed in this revised application were designed to test the hypothesis that D-pinitol may alleviate AD amyloidosis in Tg2576 mice through mechanisms 1) dependent on the reversal of insulin-resistance and/or 2) through direct modulation of mechanisms ultimately resulting in decreased generation (or increased degradation) of amyloidogenic AB peptides. In view of the evidence that the amyloid hypothesis of AD maintains that the accumulation of the AB in the brain is a critical event in disease pathogenesis, the proposed studies will provide a unique opportunity for evaluating a novel therapeutic role of D-pinitol in AD.